U.S. patent number 6,730,319 [Application Number 10/154,554] was granted by the patent office on 2004-05-04 for pharmaceutical compositions having depressed melting points.
This patent grant is currently assigned to Hoffmann-La Roche Inc.. Invention is credited to Karsten Maeder, Lukas Christoph Scheibler, Hans Steffen.
United States Patent |
6,730,319 |
Maeder , et al. |
May 4, 2004 |
Pharmaceutical compositions having depressed melting points
Abstract
The present invention relates to pharmaceutical compositions
that contain a solid pharmaceutically active compound having a
melting point .gtoreq.37.degree. C. and a fatty acid or a fatty
acid salt or a mixture of a fatty acid and a fatty acid salt. Such
composition results in a depression in melting point to
.ltoreq.37.degree. C. upon contact with an aqueous solution thereby
providing an improved outlook for absorption.
Inventors: |
Maeder; Karsten (Freiburg,
DE), Scheibler; Lukas Christoph (August,
CH), Steffen; Hans (Liestal, CH) |
Assignee: |
Hoffmann-La Roche Inc. (Nutley,
NJ)
|
Family
ID: |
8177653 |
Appl.
No.: |
10/154,554 |
Filed: |
May 23, 2002 |
Foreign Application Priority Data
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Jun 6, 2001 [EP] |
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01113792 |
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Current U.S.
Class: |
424/464; 424/451;
424/476; 424/499; 514/897; 424/502; 424/501; 424/489; 424/474;
424/452; 424/456; 424/468; 424/465 |
Current CPC
Class: |
A61P
3/06 (20180101); A61P 43/00 (20180101); A61K
9/0056 (20130101); A61K 31/365 (20130101); A61P
3/04 (20180101); A61K 9/145 (20130101); A61K
9/2013 (20130101); Y10S 514/897 (20130101); A61K
9/2054 (20130101); A61K 9/2018 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 9/14 (20060101); A61K
9/00 (20060101); A61K 31/365 (20060101); A61K
009/10 (); A61K 031/365 () |
Field of
Search: |
;424/464,465,468,474,476,451,452,489,502,400,456,499,501
;514/897 |
References Cited
[Referenced By]
U.S. Patent Documents
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|
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4540602 |
September 1985 |
Motoyama et al. |
4598089 |
July 1986 |
Hadvary et al. |
5145684 |
September 1992 |
Liversidge et al. |
5858410 |
January 1999 |
Muller et al. |
|
Foreign Patent Documents
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32 17071 |
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Nov 1983 |
|
DE |
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185 359 |
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Jun 1986 |
|
EP |
|
189 577 |
|
Aug 1986 |
|
EP |
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443 449 |
|
Aug 1991 |
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EP |
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0465 423 |
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Jan 1992 |
|
EP |
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524 495 |
|
Jan 1993 |
|
EP |
|
901 792 |
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Mar 1999 |
|
EP |
|
WO 99/33450 |
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Jul 1999 |
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WO |
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WO 00/09122 |
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Feb 2000 |
|
WO |
|
WO 00/09122 |
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Feb 2000 |
|
WO |
|
WO 00/40569 |
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Jul 2000 |
|
WO |
|
WO 01/19340 |
|
Mar 2001 |
|
WO |
|
WO 01/19340 |
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Mar 2001 |
|
WO |
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WO 01/19378 |
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Mar 2001 |
|
WO |
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WO 01/32616 |
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May 2001 |
|
WO |
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WO 01/32669 |
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May 2001 |
|
WO |
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WO 01/32670 |
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May 2001 |
|
WO |
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Other References
Kotsovolou et al., J. Org. Chem., 66, pp. 962-967 (2001). .
Mutoh et al., J. of Antibiot., 47, pp. 1369-1375 (1994). .
Charman et al., J. Pharm. Sci., 86, pp. 269-282 (1997). .
Serajuddin, A., J. Pharm. Sci., 88, pp. 1058-1066 (1999). .
Lander et al., Biotechnol. Prog., 16, pp. 80-85 (2000)..
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Bennett; Rachel M.
Attorney, Agent or Firm: Johnston; George W. Parise; John
P.
Claims
What is claimed is:
1. A solid pharmaceutical composition, which comprises: a) a solid
pharmaceutically active compound that is a lipase inhibitor and has
a melting point .gtoreq.37.degree. C., and b) a fatty acid or a
fatty acid salt or a mixture of a fatty acid and a fatty acid salt;
the pharmaceutically active compound and the fatty acid or a fatty
acid salt or a mixture of a fatty acid and a fatty acid salt being
present in amounts such that when the composition is contacted with
an aqueous solution having a pH value .ltoreq.8, the melting point
of the composition is less than the melting point of the solid
pharmaceutically active compound and .ltoreq.37.degree. C.
2. The composition according to claim 1, wherein the
pharmaceutically active compound is orlistat.
3. The composition according to claim 1, wherein the aqueous
solution is buccal or gastric fluid.
4. The composition according to claim 1, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected from the group consisting of C.sub.8 to C.sub.24
saturated and non-saturated fatty acids, salts of C.sub.8 to
C.sub.24 saturated and non-saturated fatty acids, dicarboxylic
acids, and salts of dicarboxylic acids.
5. The composition of claim 4, wherein the fatty acid is a C.sub.12
to C.sub.18 saturated fatty acid or a salt of C.sub.12 to C.sub.18
saturated fatty acid.
6. The composition according to claim 4, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected form the group consisting of lauric acid, myristic
acid, palmitic acid, stearic acid, arachidic acid and behenic acid,
and salts thereof.
7. The composition according to claim 6, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected form the group consisting of lauric acid, myristic
acid, and palmitic, and salts thereof.
8. The composition according to claim 7, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected from the group consisting or lauric acid, myristic
acid, and salts thereof.
9. The composition according to claim 4, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected from the group consisting of C.sub.12 to C.sub.18
mono- or polyunsaturated fatty acid and salts thereof.
10. The composition of claim 9, wherein the fatty acid or the fatty
acid salt or the mixture of a fatty acid and a fatty acid salt is
selected from the group consisting of palmitoleic acid, oleic acid,
elaidic acid, erucic acid, linoleic acid, gamma-linolenic acid,
alpha-linolenic acid and arachidonic acid, and salts thereof.
11. The composition of claim 10, wherein the fatty acid or the
fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected from the group consisting of oleic acid or
linoleic acid and salts thereof.
12. The composition according to claim 4, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is a C.sub.5 to C.sub.24 dicarboxylic acid or salt
thereof.
13. The composition according to claim 4, wherein the fatty acid or
the fatty acid salt or the mixture of a fatty acid and a fatty acid
salt is selected from the group consisting of glutaric acid, adipic
acid, pimelic acid, suberic acid, azelaic acid, sebacic acid,
dodecanedioc acid, and tetradecandioic acid, and salts thereof.
14. The composition according to claim 1, wherein the fatty acid or
the fatty acid salt is a mixture of two or more fatty acids or two
or more fatty acid salts.
15. The composition according to claim 1, wherein the fatty acid
salt is a ammonium, bis(2-hydroxyethyl)ammonium, diethanolammonium,
triethanolammonium, sodium, potassium, magnesium or calcium
salt.
16. The composition according to claim 15, wherein the fatty acid
salt is a sodium or potassium salt.
17. The composition according to claim 1, wherein 0.05 mg to 20 mg
fatty acid or 0.05 mg to 20 mg fatty acid salt or 0.05 mg to 20 mg
of a mixture of a fatty acid and fatty acid salt is used per 1 mg
pharmaceutically active compound.
18. The composition according to claim 17, wherein 0.5 mg to 2 mg
fatty acid or 0.5 mg to 2 mg fatty acid salt or 0.5 to 2 mg of a
mixture of a fatty acid and fatty acid salt is used per 1 mg
pharmaceutically active compound.
19. The composition according to claim 2, wherein the orlistat is
present in an amount of 10 to 240 mg.
20. The composition according to claim 19, wherein the orlistat is
present in an amount of 30 to 120 mg.
21. The composition according to claim 20, wherein the orlistat is
present in an amount of 40, 60, 80, 100, or 120 mg.
22. The composition according to claim 20, wherein the orlistat is
present in an amount of 60 to 120 mg and the fatty acid or fatty
acid salt or a mixture of a fatty acid and a fatty acid salt is
present in the amount of 20 mg to 100 mg.
23. The composition according to claim 22, wherein the orlistat is
present in an amount of 120 mg orlistat and the fatty acid or fatty
acid salt or a mixture of a fatty acid and a fatty acid salt is
present in the amount of 60 mg.
24. The composition according to claim 1 further comprising one or
more pharmaceutically acceptable excipients.
25. The composition according to claim 24, wherein the one or more
pharmaceutically acceptable excipients are selected from the group
consisting of mannitol, lactose, HPMC, talcum, sorbitol,
polyvinylpyrrolidone, lecithin, trimyristine, polyethylenglycol,
sucrose ester, polysorbate, polyoxethylenstearate, and
dimethicon.
26. The composition according to claim 25, wherein the one or more
pharmaceutically acceptable excipients are selected from the group
consisting of sucrose ester and lactose.
27. The composition according to claim 26, wherein the composition
comprises 10-240 mg of orlistat, 0.5-2000 mg of a fatty acid or a
fatty acid salt or a mixture of a fatty acid and a fatty acid salt,
5-200 mg of sucrosepalmitate.
28. The composition according to claim 27 further comprising 1.5 g
lactose.
Description
BACKGROUND OF THE INVENTION
1. Field
The present invention relates to pharmaceutical compositions. More
particularly, the invention relates to a solid pharmaceutical
composition comprising a) a solid pharmaceutically active compound
which has a melting point .gtoreq.37.degree. C. and b) a fatty acid
or a fatty acid salt or a mixture of a fatty acid and a fatty acid
salt, characterized in that the constituents of a) and b) show a
depression of their melting points to .ltoreq.37.degree. C. upon
contact with an aqueous solution.
2. Description
Many pharmaceutically active compounds exhibit low solubilities and
low dissolution rates in the biological environment. Examples
include cyclosporine, nifedipine, ritonavir, griseofulvin,
ubidecarenone, danazol, halofantrine, and tetrahydrolipstatin.
Because of the low solubility and the low dissolution rate of the
pharmaceutically active compounds, only a certain percentage of the
drug molecules is dissolved from the crystals. Undissolved drug
crystals exhibit no or very limited therapeutic activity in most
cases, independent whether a systemic action (requires drug
absorption) or a localized effect (within the lumen of the
gastrointestinal tract) is desired. Due to the low dissolution of
the active compound, higher doses have to be administrated which
might result in an increased danger of side effects. Furthermore it
has been found that the presence of food might effect the
dissolution, absorption and activity of the compound to a large
extend. As an example, the bioavailability of
alpha-tocopherol-nicotinate increased 28-fold in the fed status
compared to the fasted state [William N. Charman et al., J. Pharm.
Sci: 86, 269-282 (1997)]. Other examples include danazol,
halofantrine and etretinate. It is obvious for those skilled in the
art that the high impact of food on the dissolution of the drug
leads to an unpredictable performance of the drug. However, a low
variation of the drug dissolution is a necessity to achieve the
desired concentration for the pharmaceutically effect and to avoid
the toxic effects due to overdosing. A pharmaceutically active
compound can only be accepted if a reliable pharmacokinetic profile
can be achieved.
The need of the development of drug delivery systems to overcome
the high variation of drug dissolution has been widely recognized.
Approaches include the development of solid dispersions ("solid
solution") [A. T. M. Serajuddin, J. Pharm. Sci., 88, 1058-1066
(1999)]. The main disadvantage of this approach is the
thermodynamic instability of the supersaturated solid dispersion,
which might lead to crystallization processes leading to decreased
dissolution velocities and unpredictable bioavailbilities.
Another approach to decrease the impact of food effects is the
production of drug nanoparticules by wet-milling (U.S. Pat. Nos.
4,540,602 and 5,145,684) or High Pressure Homogenization (U.S. Pat.
No. 5,858,410). However, disadvantages include the contamination of
the product with abrasive material from the milling process.
Furthermore, both processes require the presence of suspending
liquids and the primary product is a nanosuspension and not dry
nanoparticles. The prevention of the increase in particle size due
to aggregation or Ostwald ripening is very challenging.
Stabilization of the submicrometer sized particles often requires
the time and cost intensive removal of the previously added
suspension liquid by drying or cryodrying processes. Other
disadvantages include the long processing time in wet milling
(hours to several days) and the increase in temperature and the
possible formation of radicals during the high pressure
homogenization process [R. Lander et al., Biotechinol. Prog., 16,
80-15(2000)]. Changes of drug modifications have also to be
considered as a result of the milling processes.
It must also be kept in mind, that amorphous drug molecules and
drug nanoparticles might degrade faster than the unprocessed
material due to the increased surface area. Other approaches
include the administration of the solubilized pharmaceutically
active compound. However, this approach might lead to problems
related to the chemical stability of the active compound, because
degradation processes will occur more rapidly in the solubilized
state compared to the crystalline state.
For example, lipase inhibitor molecules orlistat
(tetrahydrolipstatin), or structurally related compounds, e.g.
2-oxy-4H-3,1-benzoxanzin-4-ones as described in WO00/40569, or
2-oxo amide triacylglycerol analogues [S. Kotsovolou et al., J.
Org. Chem., 66: 962-967 (2001)] are molecules that may degrade
during storage by different mechanisms. It is well known that
degradation velocity depends to a large extent from the
physicochemical state of the active compound. In general, drug
crystals have higher chemical stability compared to drug molecules
in the amorphous or liquid state. Therefore, for good storage
stability it is desirable to incorporate drug molecules in the
crystalline form into the drug delivery system. It is, however,
also well known, that in most cases pharmacoactivity is related to
physicochemical states with high mobility, e.g. the solubilized or
molten molecule. Therefore, from the point of pharmacoactivity, the
drug molecule must be either given in a solubilized form or
transform into a solubilized form within the body.
Both stability and activity aspects have to be considered.
Therefore, the development of a drug-crystal loaded carrier which
releases a solubilized drug is the most desirable case. This
concept is easily realized for water-soluble drugs (e.g. ascorbic
acid). However, the in situ transformation of poor water-soluble
drugs remains a challenge.
The subject invention addresses this challenge.
SUMMARY OF THE INVENTION
The subject invention provides a solid pharmaceutical composition,
which comprises a solid pharmaceutically active compound that has a
melting point .gtoreq.37.degree. C., and a fatty acid or a fatty
acid salt or a mixture of a fatty acid and a fatty acid salt. The
pharmaceutically active compound and the fatty acid or a fatty acid
salt or a mixture of a fatty acid and a fatty acid salt are present
in amounts such that when the composition is contacted with an
aqueous solution having a pH value .ltoreq.8, the melting point of
the composition is less than the melting point of the solid
pharmaceutically active compound and .ltoreq.37.degree. C.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1: Light-microscopic pictures of aqueous dispersions of
orlistat/sodium laurate dispersions at varying pH-values
(37.degree. C.).
FIG. 2: Orlistat (4 mg) suspensions stabilized by fatty acid salts
(2 mg) were transferred into 5 ml of a 10% oil in water emulsion
(pH value 4.5; oil components: olive oil and cream respectively).
The dispersion underwent end-over end mixing for a desired period
of time. The oil phase was separated by cold centrifugation and the
orlistat content in the oil phase was determined by HPLC. For
comparison, an adequate experiment was also performed with a
suspension derived from XENICAL.RTM. pellets.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its
preferred embodiments. These embodiments are set forth to aid in
understanding the invention but are not to be construed as
limiting.
Surprisingly it has been found that fatty acids and/or fatty acid
salts transform with pharmaceutically active compounds, preferably
lipophilic compounds, into liquid droplets under conditions
simulating the physiological environment. The pH-value plays a
critical role in transforming a part of the fatty acid salt into
the protonated fatty acid. Protonated fatty acids depress the
melting point of certain lipophilic pharmaceutically active
compounds, e.g. lipase inhibitors like orlistat, and are able to
solubilize sufficiently amounts of the pharmaceutically active
compound. Due to the eutectic interaction between the compounds,
the melting point of both the lipophilic pharmaceutically active
compound, e.g. orlistat with a melting point of 43.degree. C. and
the fatty acid drops below body temperature (<37.degree. C.).
Therefore, the lipophilic pharmaceutically active compound, e.g.
orlistat, and the fatty acid are released in the liquid phase
although their (individual) melting points may exceed the body
temperature.
Accordingly, the present invention relates to a solid
pharmaceutical composition comprising
a) a solid pharmaceutically active compound which has a melting
point .gtoreq.37.degree. C. and
b) a fatty acid or a fatty acid salt or a mixture of a fatty acid
and a fatty acid salt, and
c) optionally additional pharmaceutically acceptable
excipients,
characterized in that the constituents of a) and b) show a
depression of their melting points to .ltoreq.37.degree. C. upon
contact with an aqueous solution.
This invention provides pharmaceutical compositions that are able
to transform the active ingredient after oral ingestion from a
solid form with a melting point of the active ingredients
.gtoreq.37.degree. C. to a liquid form, which is released. The
manufacturing of the composition excludes the disadvantages of
other formulation approaches, such as:
the formation of supersaturated compositions (as in "solid
solutions")
high mechanical energy for particle disruption, which may lead to
contamination with abrasive material (as by wet milling, high
pressure homogenization) and/or radical formation
the formation of different drug polymorphs or pseudopoylmorphs due
to the processing
increased degradation rates due to the liquid/semiliquid form of
the active compound.
The in-situ transformation of the active compound into a liquid
combines the advantages of good storage stability of drug crystals
(no drug solubilization, no supersaturation, no radical formation
due to particle disruption, preserved particle size) with the high
activity of compositions which release the active molecule in the
liquid form.
In the present invention the term "pharmaceutically acceptable" as
used herein stands for that the buffer or salts are acceptable from
a toxicity viewpoint.
The term "pharmaceutically acceptable salts" as used herein stands
for salts of fatty acids with an organic or inorganic base such as
ammonium hydroxide, diethanol-ammonium hydroxide,
triethanolammonium hydroxide, (hydroxyethyl)ammonium hydroxide,
sodium hydroxide, potassium hydroxide, etc. For the present
compositions pharmaceutically acceptable salts of the fatty acids
mentioned are sodium, potassium, magnesium and calcium salts,
preferably sodium and potassium salts.
The term "pharmaceutically active compound" refers to molecules
with low water solubility. Preferably the pharmaceutically active
compound is a lipophilic compound, more preferably a lipase
inhibitor and most preferably orlistat.
The term "fatty acid" comprises one single fatty acid as well as a
mixture of two or more fatty acids as defined below.
The term "fatty acid salt" comprises one single fatty acid salt as
well as a mixture of two or more fatty acid salts as defined
below.
The term "lipophilic compounds," as defined herein, stands for
compounds soluble in organic solvents. While the compounds suitable
for use here may have minimal solubility in water, their solubility
in organic solvents is substantially greater. Generally, the
solubility of a lipophilic compound in a organic solvent should be
high enough to prepare at least 1% solution of the compound in the
organic solvent.
The composition shows "eutectic behavior" in that sense, that the
melting point of the composition in the aqueous phase below pH 8 is
lower than the melting point of each of the single components.
A "lipophilic compound" may be any lipophilic pharmaceutical active
compound desirable in oral compositions as long as the compound
satisfies the solubility requirements outlined above.
In a preferred embodiment of the present invention the
pharmaceutically active compound has a melting point
.gtoreq.37.degree. C.
The pharmaceutically active compounds are characterized by low
water solubility. Preferably, the pharmaceutically active compound
is a lipophilic compound, e.g. orlistat. Examples for these
compounds are antibiotics, lipophilic vitamins and their
derivatives, and lipase inhibitors such as orlistat.
The term "lipase inhibitor" refers to compounds which are capable
of inhibiting the action of lipases, for example gastric and
pancreatic lipases, e.g. orlistat.
Orlistat (tetrahydrolipstatin) is a well known example for a lipase
inhibitor (formula (I)). ##STR1##
Orlistat is useful in the control or prevention of obesity and
hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986,
which also discloses processes for making orlistat. Additional
processes for the preparation of orlistat are disclosed in European
Patent Applications Publication Nos. 185,359, 189,577, 443,449, and
524,495.
Other lipase inhibitors include a class of compound commonly
referred to as panclicins. Panclicins are analogues of orlistat
[Mutoh et al., J. Antibiot., 47(12):1369-1375 (1994)]. In addition,
the term "lipase inhibitor" also refers to
2-oxy-4H-3,1-benzoxazin-4-ones which have been described in
International Patent Application WO00/40569 (Alizyme Therapeutics
Ltd.), e.g. 2-decyloxy-6-methyl-4H-3,1-benzooxazin-4-one,
6-methyl-2-tetradecyloxy-4H-3,1-benzoxazin-4-one, and
2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one and other
oxetanones described for example in International Patent
Applications WO01/32616, WO01/32669 and WO01/32670. Most
preferably, the term "lipase inhibitor" refers to orlistat.
The preferred compositions have eutectic behavior in aqueous
solutions at pH values .ltoreq.8. An example for this kind of
solution is buccal or gastric fluid.
In a further preferred embodiment of the present invention, the
term "fatty acid or the fatty acid salt or the mixture of a fatty
acid and a fatty acid salt" refers to C.sub.8 to C.sub.24,
preferably a C.sub.12 to C.sub.18 saturated and non-saturated fatty
acids, and salts thereof. The above term also refers to
dicarboxylic acids and salts thereof. The corresponding fatty acid
salts may be selected from the group consisting of the
corresponding ammonium, bis(2-hydroxyethyl)ammonium,
diethanolammonium, triethanolammonium, sodium, potassium, magnesium
and calcium salt, preferably the corresponding sodium or potassium
salt, and most preferably the corresponding sodium salt.
The fatty acids, fatty acids salts and mixtures thereof are known
in the art and commercially available (DM Small: Handbook of lipid
research. Vol. 4, Plenum Press New York, 1986; Fatty acid sources:
Aldrich, Sigma, Fluka, Karlshamns, Indofine, Cognis, Croda).
The preparation of mixtures of fatty acids, of fatty acids salts
and of fatty acids and fatty acids salts may be performed according
to methods known in the art, e.g. dry mixing, melting with or
without solvent, etc.
In a preferred embodiment of the present invention the fatty acid
or a fatty acid salt or the mixture of a fatty acid and a fatty
acid salt may be selected from C.sub.8 to C.sub.24, preferably a
C.sub.12 to C.sub.18 saturated fatty acids and salts thereof, e.g.
selected from the group of a consisting of lauric acid, myristic
acid, palmitic acid, stearic acid, arachidic acid and behenic acid;
more preferably lauric acid, myristic acid and palmitic acid, and
most preferably lauric or myristic acid and salts thereof.
In a further preferred embodiment of the invention the fatty acid
or a fatty acid salt or the mixture of a fatty acid and a fatty
acid salt may be selected from C.sub.8 to C.sub.24, preferably a
C.sub.12 to C.sub.8, mono-or polyunsaturated fatty acids and salts
thereof, e.g. selected from the group consisting of palmitoleic
acid, oleic acid, elaidic acid, erucic acid, linoleic acid,
gamma-linolenic acid, alpha-linolenic acid and arachidonic acid,
preferably oleic acid or linoleic acid and salts thereof.
Further, the fatty acid or a fatty acid salt or the mixture of a
fatty acid and a fatty acid salt may be selected from dicarboxylic
acids from C.sub.5 to C.sub.24., e.g. glutaric acid, adipic acid,
pimelic acid, suberic acid, azelaic acid, sebacic acid,
dodecanedioc acid, and tetradecandioic acid and/or a salt
thereof.
The fatty acid (or the corresponding salt) may comprise one single
fatty acid (or the corresponding salt) as well as a mixture of two
or more fatty acids (or the corresponding salts) as described
above.
The corresponding fatty acid salt may be an ammonium,
bis(2-hydroxyethyl)ammonium, diethanolammonium, triethanolammonium,
sodium, potassium, magnesium or calcium salt, preferably a sodium
or potassium salt.
The preferred ratio (w/w) between pharmaceutically active compound
and fatty acid or a fatty acid salt or a mixture of a fatty acid
and a fatty acid salt is as follows: The composition may comprise
0.05 mg to 20 mg fatty acid or 0.05 mg to 20 mg fatty acid salt or
0.05 mg to 20 mg of a mixture of a fatty acid and a fatty acid salt
is used per 1 mg pharmaceutically active compound. Preferably the
composition comprises 0.5 mg to 2 mg fatty acid or 0.5 mg to 2 mg
fatty acid salt or 0.5 to 2 mg of a mixture of a fatty acid and a
fatty acid salt is used per mg pharmaceutically active compound.
The preferred pharmaceutically active compound in this composition
is a lipase inhibitor, most preferably orlistat.
In case in addition to the effect of a lipase inhibitor an
additional inhibition of gastric lipases should be achieved a
higher amount of fatty acids/fatty acid salts may be advisable.
This additional inhibition of gastric lipases by providing
additional fatty acids or fatty acids salts or a mixture of at
least one fatty acid and at least one fatty acid salt is known in
the art and has been described e.g. in European Patent Application
No. 901,792 and German Patent Application No. 3,217,071. In this
case the ratio between lipase inhibitor and fatty acid or fatty
acid salt and a mixture of fatty acid salt may change to up to 1:20
(w/w).
For lipase inhibitors as described above, e.g. orlistat, preferred
compositions comprise 10 to 240 mg, more preferably 40 to 120 mg,
e.g. 40, 60, 80, 100, or 120 mg.
Especially preferred compositions comprise 60 to 120 mg orlistat
and 30 mg to 100 mg fatty acid or fatty acid salt or a mixture of
fatty acid and fatty acid salt. For example a composition as
defined above may comprise 120 mg orlistat and 60 mg fatty acid or
fatty acid salt or a mixture of a fatty acid and a fatty acid
salt.
Each dosage unit of the above pharmaceutical compositions can
obtain the daily doses of the pharmaceutically active compound or
may contain a fraction of the daily dose, such as one-third of the
doses. Alternatively, each dosage unit may contain the entire dose
of one of the compounds, and a fraction of the dose of the other
compound. In such case the patient would daily take one of the
combination dosage units, and one or more units containing only the
other compound.
Orlistat is preferably orally administered from 30 to 800 mg per
day in divided doses two to three times per day. Preferred is
wherein from 120 to 240 mg, most preferably 180 mg per day of a
lipase inhibitor is administered to a subject, preferably in
divided doses two or, particularly, three times per day. Generally,
it is preferred that the lipase inhibitor has to be administered
within about one or two hours of ingestion of a meal containing
fat. Generally, for administering a lipase inhibitor as defined
above it is preferred that treatment be administered to a human who
has a strong family history of obesity or has obtained a body mass
index of 25 or greater.
The compositions of the present invention may be administered to
humans in conventional oral compositions, such as, tablets, coated
tablets, hard and soft gelatin capsules, emulsions or suspensions.
Examples of carriers which can be used for tablets, coated tablets,
dragees, hard gelatin capsules and sachets are lactose, other
sugars and sugar alcohols like sorbitol, mannitol, maltodextrin, or
other fillers; surfactants like sodium lauryl sulfate, Brij 96,
Tween 80 or sucrose esters; disintegrants like sodium starch
glycolate, maize starch or derivatives thereof; polymers like
povidone, crospovidone; lubricants like talc; stearic acid or its
salts and the like. Moreover, the pharmaceutical preparations can
contain preserving agents, solubilizers, stabilizing agents,
wetting agents, emulsifying agents, sweetening agents, coloring
agents, flavoring agents, salts for varying the osmotic pressure,
buffers, coating agents and antioxidants. They can also contain
still other therapeutically valuable substances. The formulations
may conveniently be presented in unit dosage form and may be
prepared by any methods known in the pharmaceutical art.
Especially, the above compositions may comprise one or more
pharmaceutically acceptable excipients selected from the group
consisting of mannitol, lactose, HPMC, talcum, sorbitol,
polyvinylpyrrolidone, lecithin, trimyristine, polyethylenglycol,
sucrose ester, polysorbate, polyoxethylenstearate, and dimethicone,
preferably a sucrose ester, e.g. sucrosepalmitate and/or
lactose.
Oral dosage forms are the preferred compositions for use in the
present invention and these are the known pharmaceutical forms for
such administration, for example tablets, capsules or sachets. The
pharmaceutically acceptable excipients (diluents and carriers) are
known in the pharmacist's art. Tablets may be formed from a mixture
of the active compounds with fillers, for example calcium
phosphate; disintegrating agents, for example maize starch,
lubricating agents, for example magnesium stearate; binders, for
example microcrystalline cellulose or polyvinylpyrrolidone and
other optional ingredients known in the art to permit tabletting
the mixture by known methods. Similarly, capsules, for example hard
or soft gelatin capsules, containing the active compound with or
without added excipients, may be prepared by known methods. The
contents of the capsule may be formulated using known methods so as
to give sustained release of the active compound. For example, the
tablets and capsules may conveniently each contain the amounts of a
pharmaceutically active compound and a fatty acid or a fatty acid
salt or a mixture of a fatty acid and a fatty acid salt as
described above.
The oral dosage form may be a chewable tablet comprising 10-240 mg
of orlistat, 0.5-2000 mg of fatty acid or a fatty acid salt or a
mixture of fatty acid salt with fatty acid, 5-200 mg of
sucrosepalmitate and optionally 1.5 g of lactose.
In the compositions of the present invention the active compounds
may, if desired, be associated with other compatible
pharmacologically active ingredients. Optionally vitamin
supplements maybe administered with the compounds of the present
invention.
The invention also refers to a process for preparing a composition
as described above, comprising mixing a pharmaceutically active
compound thereof with fatty acid or a fatty acid salt or a mixture
of a fatty acid salt with a fatty acid and one or more
pharmaceutically acceptable diluents and/or carriers.
The invention also provides the use of the above composition in the
manufacture of a medicament for the treatment and prevention of
obesity. Additionally, it provides the above compositions for use
in the treatment and prevention of obesity.
In addition, the present invention refers to a method of treatment
of obesity in a human in need of such treatment which comprises
administration to the human of a pharmaceutically active compound
as defined above and a fatty acid or a fatty acid salt or a mixture
of a fatty acid and a fatty acid salt, and optionally additional
pharmaceutical acceptable excipients.
The invention also refers to the use of a composition as defined
above in the treatment and prevention of obesity.
Another embodiment of the present invention refers to a process for
preparing a composition as defined above, comprising mixing a
pharmaceutically active compound as defined in claim 1 with a fatty
acid or fatty acid salt or a mixture of a fatty acid and a fatty
acid salt, and optionally, or more pharmaceutically acceptable
diluent and/or carrier.
Further the invention refers to a kit for treatment of obesity,
said kit comprising a first component which is a lipase inhibitor
and a second component which is a fatty acid or fatty acid salt or
a mixture of a fatty acid and a fatty acid salt unit dosage
forms.
Another embodiment relates to the use of a composition as defined
above in the manufacture of medicaments useful for the treatment
and prevention of obesity and to a method of treatment of obesity
in a human in need of such treatment which comprises administration
to the human of a therapeutically effective amount of a lipase
inhibitor and a fatty acid or fatty acid salt or a mixture of a
fatty acid and a fatty acid salt as defined above.
The invention also refers to a lipase inhibitor and a fatty acid or
fatty acid salt or a mixture of a fatty acid and a fatty acid salt
as defined above for the treatment and prevention of obesity.
The invention will be better understood by reference to the
following examples which illustrate but do not limit the invention
described herein.
EXAMPLES
General remarks: All compounds used in the examples are
commercially available. Melting points of the mixtures were
determined by DSC (differential scanning calorimeter) and hot stage
microscopy.
Example 1
Orlistat/fatty Acid Salt
COMPOSITION I sodium capyrylate 40 mg orlistat 40 mg phosphate
buffer (Sorensen), pH 7.4 1 ml
The above composition consists of orlistat/fatty acid droplets in
an aqueous solution (pH <8) at 37.degree. C. No crystals are
detectable.
Example 2
Orlistat/fatty Acid Salt
COMPOSITION II sodium laurate 50 mg orlistat 100 mg water 3 ml
A suspension was formed by mixing the ingredients in water at
37.degree. C. The pH was adjusted stepwise with 0.1 N HCl. The
samples were investigated by light microscopy and the following
results were obtained (FIG. 1).
a) >pH 9.4: only orlistat crystals
b) pH 8.54: both orlistat crystals and fatty acid/orlistat
droplets
c) <pH 8.15: only fatty acid/orlistat droplets
Decreasing pH-values lead to the formation of orlistat/lauric
acid/sodium laurate droplets. At pH values of 8.15 and lower, all
of the orlistat molecules are present in their liquid form.
DSC (differential scanning calorimeter) of orlistat/fatty acid in
water demonstrated that the melting point of orlistat/lauric sodium
laurate was shifted to 32.degree. C. in aqueous solution for pH
values <8.
Example 3
Orlistat/fatty Acid Salt
COMPOSITION III sodium oleate 50 mg orlistat 100 mg water 3 ml
The ingredients were mixed in water at 37.degree. C. After pH
adjustment with 0.1 N HCl to pH 7 the orlistat crystals disappeared
and orlistat/oleic acid droplets were formed.
Example 4
Orlistat/fatty Acid
COMPOSITION IV myristic acid 60 mg orlistat 120 mg water 3 ml
The ingredients were mixed in water at 37.degree. C. Microscopic
investigation showed the presence of orlistat/myristic acid
droplets; no orlistat crystals were seen.
Example 5
Orlistat/fatty Acid
COMPOSITION V palmitic acid 60 mg orlistat 120 mg water 3 ml
The ingredients were mixed in water at 37.degree. C. Microscopic
investigation showed the presence of orlistat/palmitic acid
droplets; no orlistat crystals were seen.
Example 6
Orlistat/fatty Acid/fatty Acid Salt
Preparation of the fatty acid sodium salt complex:
COMPOSITION V sodium laurate 30 mg lauric acid 30 mg orlistat 120
mg (water) (0.1 ml)
A complex between sodium laurate and lauric acid is formed, which
can be achieved by standard procedures, e.g. intensive mixing the
substances at elevated Temperatures (>40), with or without the
addition of solvents (water, ethanol) or drying of the solubilized
fatty acid/fatty acid salt mixture.
The lauric acid/sodium laurate complex is mixed with orlistat by
commonly used equipment until homogeneity is achieved. The
composition is dried at 30.degree. C. in Vacuum to constant
weight.
Exposure of the dried mixture to buffer solutions pH <8 at
37.degree. C. (e.g. artificial gastric juice led to the formation
of liquid orlistat-fatty acid droplets.
Example 7
Orlistat/fatty Acid/fatty Acid Salt
Preparation of the fatty acid sodium salt complex:
COMPOSITION V sodium myristate 30 mg myristic acid 30 mg orlistat
120 mg (water) (0.1 ml)
A complex between sodium myristate and myristic acid is formed,
which can be achieved by standard procedures, e.g. intensive mixing
the substances at elevated Temperatures (>40), with or without
the addition of solvents (water, ethanol) or drying of the
solubilized fatty acid/fatty acid salt mixture.
The myristic acid/sodium myristate complex is mixed with orlistat
by commonly used equipment until homogeneity is achieved. The
composition is dried at 30.degree. C. in Vacuum to constant
weight.
Exposure of the dried mixture to buffer solutions pH <8 at
37.degree. C. (e.g. artificial gastric juice USP) leads to the
formation of liquid orlistat/myristic acid--myristate droplets.
Example 8
Transfer Efficacy of Orlistat/Fatty Acid Salt
Orlistat (4 mg) suspensions stabilized by fatty acid salts (2 mg)
were transferred into 5 ml of a 10% oil in water emulsion (pH value
4.5; oil components: olive oil and cream respectively). The
dispersion underwent end-over end mixing for a desired period of
time. The oil phase was separated by cold centrifugation and the
orlistat content in the oil phase was determined by HPLC. For
comparison, an adequate experiment was also performed with a
suspension of XENICAL.RTM..
The results indicate (FIG. 2) that in situ forming fatty acid
derived orlistat emulsions have a higher efficacy (up to 20-fold)
to transfer orlistat into oil compared to XENICAL.RTM.. In addition
to a general higher transfer efficacy and in contrast to
XENICAL.RTM., orlistat is transferred into different kind of oils
(cream: emulsified and casein covered oily droplets; olive oil:
unprotected oil) at comparable rates. Therefore, a dose reduction
and a decreased food dependency can be expected.
Example 9
Chewable Tablet Composition--Fatty Acid--Orlistat
COMPOUND AMOUNT orlistat 60 g myristic acid 30 g mannitol 400 g
lactose 400 g talcum 10 g
Orlistat and myristic acid are melted together at 50.degree. C.
Mannitol and lactose are added and the mixture is cooled to RT
(room temperature) under continuously stirring. Talcum is added and
homogeneously distributed. The powder is pressed into tablets of
960 mg weight (=orlistat content of 120 mg). In vitro release
experiments demonstrate the release of orlistat droplets at
37.degree. C. into the following release media: phosphate buffer,
pH7.4; citrate buffer, pH 4.5; 0.1 M HCl, pH 1.0.
Example 10
Chewable Tablet Composition--Fatty Acid--Orlistat
COMPOUND AMOUNT orlistat 120 g myristic acid 30 g PEG40-Stearate 12
g lactose 15 g
Orlistat and myristic acid are melted together at 50.degree. C.
Sucrosepalmitate and lactose are added and the mixture is cooled to
RT under continuously stirring. The powder is pressed into tablets
of 960 mg weight (=orlistat content of 120 mg). In vitro release
experiments demonstrate the release of orlistat droplets at
37.degree. C. into the following release media: phosphate buffer,
pH7.4; citrate buffer, pH 4.5; 0.1 M HCl, pH 1.0.
Example 11
Tablet Composition--Fatty Acid Salt--Orlistat
COMPOUND AMOUNT orlistat 120 g sodium laurate 30 g mannitol 80 g
HPMC 3cp 60 g
The ingredients are mixed together with stepwise addition of a
(50:50% m/m) ethanol/water mixture (0.2 ml/g). The formed granules
are dried in Vacuum at 30.degree. C. to constant weight and pressed
into tablets (each containing 120 mg orlistat). In vitro release
experiments demonstrate the release of orlistat droplets at
37.degree. C. into the following release media: phosphate buffer,
pH7.4; citrate buffer, pH 4.5; 0.1 M HCl, pH 1.0.
Example 12
Tablet Composition--Fatty Acid/Fatty Acid Salt--Orlistat
COMPOUND AMOUNT orlistat 120 g myristic acid 15 g sodium myristate
15 g mannitol 80 g HPMC 3cp 60 g
The ingredients are mixed together with stepwise addition of a
(50:50% m/m) ethanol/water mixture (0.2 ml/g). The formed granules
are dried in Vacuum at 30.degree. C. to constant weight and pressed
into tablets (each containing 120 mg orlistat). In vitro release
experiments demonstrate the release of orlistat droplets at
37.degree. C. into the following release media: phosphate buffer,
pH7.4; citrate buffer, pH 4.5; 0.1 M HCl, pH 1.0.
Upon reading the present specification, various alternative
embodiments will become obvious to the skilled artisan. These
variations are to be considered within the scope and spirit of the
subject invention, which is only to be limited by the claims that
follow and their equivalents.
* * * * *